Expression of interleukin‐6 in osteoarthritic chondrocytes and effects of fluid‐induced shear on this expression in normal human chondrocytes <i>in vitro</i>

Mohtai, M; Gupta, Malini; Donlon, B. S.; Ellison, B.; Cooke, John P.; Gibbons, Gary H.; Schurman, David J.; Smith, Robert L.

doi:10.1002/jor.1100140112

Cited by 96 publications

(77 citation statements)

References 56 publications

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“…The confluent cells on glass slides were either kept as static controls or subjected to shear stress for 1.5 or 24 hours followed by RNA isolation and analysis. Previous studies (16,52,68) have demonstrated that chondrocyte responses were elicited by shear stress at such durations and a 1.6-Pa amplitude, which was used in the current study. The MMP-9 gene was induced in cells sheared for 1.5 and 24 hours (Fig.…”

Section: Resultsmentioning

confidence: 99%

Biomechanical regulation of matrix metalloproteinase‐9 in cultured chondrocytes

Jin

Sah

et al. 2000

Journal Orthopaedic Research

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Summary:Abnormal mechanical loading of joints may induce degeneration of articular cartilage. Shear stress is one mode of mechanical loading that may regulate chondrocyte metabolism. We investigated the mechanism by which shear stress induccs the gene encoding matrix metalloproteinase-9, a mediator of the progressive degradation of articular cartilage in ostcoarthritis. In vifro experiments using passaged rabbit chondrocytes in monolayer culture subjected to a shear stress of 16 dynicn? (1.6 Pa) in a flow channel showed increased expression of the matrix mctalloproteinase-9 gcne. The induction of matrix metalloproteinase-9 appeared to depend on a region in the 5' promoter of the gcnc that contains a 12-0-tetradecanoylphorbol 13-acetateresponsive element. Transfection experiments using a construct containing a luciferase reporter driven by a 12-0-tetradecanoylphorbol 13-acetate-responsive clement indicated that shear stress activated a 12-0-tetradecanoylphorbol 13-acetate-responsive element-mediated transcription in chondrocytes. Similar experiments showed that shear stress induced a matrix metalloproteinase-9 promoter construct (matrix metalloproteinase-9-luciferase). Shear stress activated c-Jun NH1-terniinal kinasc, cxtraccllular signal-regulated kinase. and p3X. 'Transfection of matrix inetalloproteinase-9-lucifcrase together with thc dominant negative mutant of c-.Tun NH,-terminal kinase. hut not with that of cxtraccllular signal-regulated kinase or p38. attenuated the shearinduced matrix metalloproteinasc-9 promoter activity. In addition. transfection of constructs encoding dominant negative mutants o C Ras. Rac. and Cdc42 attenuated the induction of c-Jun transcriptional activity by shear stress. Thus. shear stimulation of chondrocytes stimulates Kas, Rac, and Cdc42, which subsequcntly activate c-Jun NH?-terminal kinasc to induce a 12-0-tetradecanoylphorhol 13-acetate-responsive clementmcdiatcd expression of matrix metalloproteinase-9. ~The metabolic activity of chondrocytes is regulated by mechanical factors (28). Such biomechanical regulation map affect the balance between anabolic and catabolic processes in articular cartilage. In osteoarthritis, a metabolic imbalance results in lie1 matrix degradation and the degeneration of articular cartilage (59). Many in vivo and in vitro studies have examined the effect of biomechanical stimuli on the synthesis of matrix proteins by chondrocytes (28). However. relatively few studies have analyzed the extracellular or cellular mechanisms by which mechanical stimuli may alter cartilage matrix degradationincluding the modulation of matrix protcinascs and their inhibitors (68)-and thereby contribute to the initiation or progression of osteoarthritis.In osteoarthritis, the synthesis of matrix metalloprotcinascs (MMPs) by chondrocytes is incrcased (20) and the balancc betwcen proteases and protease

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Section: Resultsmentioning

confidence: 99%

Biomechanical regulation of matrix metalloproteinase‐9 in cultured chondrocytes

Jin

Sah

et al. 2000

Journal Orthopaedic Research

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“…In addition, cytokine genes have a potential role in controlling the catabolic/anabolic balance of articular cartilage. Several cytokines are involved in cartilage metabolism and are synthesized by synovial cells and cartilage chondrocytes, among them IL-6 (Mohtai et al, 1996). IL-6 is believed to be one of the crucial factors in joint destruction, being a pleiotropic pro-inflammatory cytokine that is markedly upregulated at times of tissue inflammation.…”

Section: Discussionmentioning

confidence: 99%

Association of the IL-6 -174G/C gene polymorphism with knee osteoarthritis in a Thai population

Honsawek¹,

Deepaisarnsakul²,

Tanavalee³

et al. 2011

Genet. Mol. Res.

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ABSTRACT. Osteoarthritis is a chronic progressive degenerative joint disease characterized by age-related regressive change in articular cartilage. A single nucleotide polymorphism has been described at position -174 of the interleukin-6 (IL-6) promoter region, leading to three possible genotypes, GG, GC, and CC. We investigated a possible association of the IL-6 -174G/C gene polymorphism with knee osteoarthritis in a Thai population. Genotype distributions and allelic frequencies of the IL-6 -174G/C polymorphism were investigated in 115 knee osteoarthritis patients and 100 healthy controls. Genotyping was performed using PCR-RFLP. The genotype distribution of IL-6 was 79 GG, 36 GC, 0 CC in knee osteoarthritis patients and 88 GG, 12 GC, 0 CC in controls. The frequency of the GC genotype in subjects with knee osteoarthritis was higher than in controls (P < 0.001). Logistic regression analysis showed Association of IL-6 -174G/C polymorphism with knee OA that the GC genotype was independently associated with increased risk of knee osteoarthritis (odds ratio = 3.3, 95% confidence interval = 1.6-6.9, P = 0.001). These findings suggest that the -174G/C polymorphism of the IL-6 gene promoter plays a role in the pathogenesis of knee osteoarthritis.

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“…Induction of IL-6 in response to different types of mechanical stresses has been reported in several cell types, such as vascular endothelial cells [41][42][43], vascular smooth muscle cells [44], cardiac myocytes [45], lung fibroblasts [46], and chondrocytes [47]. To investigate whether mechanical stress associated with mild fluctuations in IOP similar to those that may occur in normal physiologic conditions [7] could induce the production of IL-6 in TM cells, we selected a cyclic stretch regimen of 5% elongation per second as an in vitro model.…”

Section: Discussionmentioning

confidence: 99%

Induction of IL-6 expression by mechanical stress in the trabecular meshwork

Liton

Luna

Bodman

et al. 2005

Biochemical and Biophysical Research Communications

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The trabecular meshwork (TM)/Schlemm's canal (SC) outflow pathway is the tissue responsible for maintaining normal levels of intraocular pressure. In the present study, we investigate the effects of mechanical stress on the expression of IL-6 in the TM meshwork, as well as the effects of this cytokine on outflow pathway function. Application of cyclic mechanical stress to human TM primary cultures resulted in a statistically significant increase in both secretion and transcription of IL-6, compared to nonstressed controls. Addition of TGF-β1, which has been reported to be upregulated in TM cells under mechanical stress, also induced a significant activation of both the transcription and secretion of IL-6. Moreover, anti-TGF-b1 antibodies partially blocked the stretch-induced IL-6 production. Injection of IL-6 into perfused porcine anterior segments resulted in a 30% increase in outflow facility, as well as increased permeability through SC cell monolayers. These results suggest a role for IL-6 in the homeostatic modulation of aqueous humor outflow resistance. KeywordsTrabecular meshwork; Interleukin-6; Mechanical stress; TGF-β1; glaucomaThe trabecular meshwork (TM)/Schlemm's canal (SC) outflow pathway system constitutes the main route by which the aqueous humor exits the anterior chamber of the eye [1]. Maintenance of appropriate levels of aqueous humor outflow resistance through this pathway is critical in sustaining normal levels of intraocular pressure (IOP) [2,3]. Although it has been hypothesized that the TM/SC outflow pathway may respond to transient changes in IOP by altering its resistance to aqueous humor [4][5][6], thereby maintaining normal IOP levels, there is little experimental evidence explaining such potential homeostatic mechanisms.As a result of cyclic fluctuations of IOP with each heartbeat, the conventional outflow pathway is subjected to continuous cycles of stretch and relaxation that might be involved in tissue homeostasis and, consequently, in IOP regulation [7]. It has been well described that changes in IOP exert dramatic effects on the morphology of the outflow pathway [8][9][10][11][12]. Increased IOP results in distention and stretching of the outflow pathway and its contained cells, while decreased IOP leads to relaxation of the tissue. It has also been demonstrated that mechanical stress can trigger certain responses in TM cells, including cytoskeletal changes, induction of gene expression, and activation of regulatory pathways [13][14][15][16][17][18][19][20][21] One of the reported responses to increased IOP in perfused human anterior segments observed by gene array analysis is an increase in interleukin-6 (IL-6) mRNA [16]. IL-6 is well known to increase the permeability of vascular endothelium through effects on the paracellular pathway, induction of matrix metalloproteinases (MMPs), and vesicular trafficking [22][23][24]. This array of effects mediated by IL-6 suggests that this cytokine could affect aqueous humor outflow resistance in the outflow pathway by increasing ...

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Expression of interleukin‐6 in osteoarthritic chondrocytes and effects of fluid‐induced shear on this expression in normal human chondrocytes in vitro

Cited by 96 publications

References 56 publications

Biomechanical regulation of matrix metalloproteinase‐9 in cultured chondrocytes

Biomechanical regulation of matrix metalloproteinase‐9 in cultured chondrocytes

Association of the IL-6 -174G/C gene polymorphism with knee osteoarthritis in a Thai population

Induction of IL-6 expression by mechanical stress in the trabecular meshwork

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